Inquiring minds want to know

How does pot work?

WHAT MAKES DOPE so dope? Scientists around the world are searching for answers.

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Cannabis research "has become a very active field," says pharmacology expert Leslie L. Iversen, who has written a book on the subject. At the University of Washington, for example, anesthesiology professor Dr. Ken Mackie oversees a six-person lab where the biochemical effects of the drug are studied. "There are maybe 50 groups in the country at work on this," he says.

However, before you decide to switch careers, you should know that the actual lab work involves mostly petri dish analysis of minute chemical reactions—not dudes crashed out on sofas taking firsthand "field notes." Still, Mackie says, "It's a very attractive field." Unlike most academics laboring in the obscurities of neuroscience, "You can go to parties and tell people what you do, and they're interested," he says. Mackie rarely has trouble locating UW undergrads to help staff his lab. And he says his clinical patients over at Harborview are always eager to volunteer when they learn his specialty. But, he jokes, "When they find out it involves donating a slice of their brain, they become much less interested."

Nearly 40 years ago, researchers figured out that a compound called THC was the element of cannabis primarily responsible for marijuana's pharmacological effects. THC is most concentrated in the plant's female flowering heads, or buds. But how exactly does THC work? Why does it produce munchies, red-eye, and that unique stoner mind-set known to researchers as "fatuous euphoria"?

Some of these puzzles have begun to be solved. For instance, THC causes a relaxation of the smooth muscles in the arteries, leading to "vasodilatation." This effect is most readily seen in the blood vessels of the eye, which is why workday dope smokers need Visine.

On the other hand, uncontrollable laughter remains largely a mystery. "This effect of the drug is hard to explain," writes Iversen in his book The Science of Marijuana (2000, Oxford University Press), "as we know so little about the brain mechanisms involved." Ordinary laughter is, from the biochemical/neurological point of view, still poorly understood, let alone stoned laughter.

Nonetheless, says Dr. Iversen in an interview, "We know a whole lot more about THC now than we did 10 years ago." The most important discovery was of a special receptor in cells for THC, a kind of ready-made biological slot for exactly what marijuana has to deliver. This finding established that the drug was not just "dissolving in the membranes of brain cells in a nonspecific sort of way," says Iversen. "There's a very specific receptor protein."

The places in the body with THC receptors seem to correspond with the drug's effects, though not always. "One of the key areas in the [brain's] frontal cortex has a high density of [such] receptors," says Iversen, "and that may have something to do with impairment in what brain scientists call 'executive' functions—short-term memory, learning, the ability to take in information, plan ahead, make complicated future arrangements. That ties in reasonably well with actual experience," he adds dryly.

On the other hand, there are also THC receptors in the white blood cells of our immune system, which do not seem to have anything to do with the experience of intoxication and whose function is "largely obscure," Iversen says.

There are no THC receptors in the brain stem, which controls critical functions like respiration, according to the UW's Dr. Mackie. That's partly why you never hear of someone fatally OD'ing on pot. "THC is not wired to be as harmful," Mackie says.

So why does marijuana seem to have such different effects on different users? "THC may not bind as well in some people," says Mackie, "and some people may break it down more quickly than others. That's an area that hasn't been explored much."

AS A RESULT of these discoveries, "a lot of interesting things are coming out from which new medical approaches may emerge," says Iversen. One long-standing hope is that the beneficial effects of marijuana can be isolated from the high—a separation that has so far proved impossible. That might help assuage Republican legislators, as well as make the drug more palatable to some patients. "These are not necessarily nice experiences," notes Iversen. "Inexperienced users can be frightened and anxious."

Dr. Mackie's current research is aimed at understanding how our bodies develop tolerance. He notes that people taking the drug regularly for medicinal purposes often have to smoke increasing amounts for the same benefit, thereby becoming more subject to its intoxicating side effects. "If we understand how tolerance develops, we can develop strategies to get around that," he says.

His research protocol does not involve administering a steadily graduated number of bong hits to journalist volunteers. Instead, he delivers minute quantities of THC to incubated frogs' eggs, then measures the electrical current flowing across the membranes of the cell.

Mackie gets his THC directly from the National Institute of Drug Abuse, which has a program for supplying controlled substances to researchers. The stuff is free, says Mackie, "so that helps the research budget." But it can only be used for basic science in the lab, not in humans. In this country, "all testing of medical benefits is virtually impossible," he says. "It's much easier to do human experimentation in Europe. Most of the really interesting trials are done there."

Scientists do not imagine that the body's THC receptors are simply waiting for their owner to spark up a bowl; the proteins must have some other function. It was recently discovered that the body has its own cannabislike chemicals, analogous to THC, which occur naturally and attach to these same cell receptors.

"What THC is doing is impacting on— or hijacking, if you like—a natural system that's there physiologically for some reason that we don't really understand," says Iversen. Opiate drugs like heroin likewise have been found to mimic naturally occurring equivalents. "It's an exactly parallel story," says Iversen. "We start by studying a psychoactive plant-derived drug and discover a whole regulatory system in the brain that we didn't know existed."

The first known of these natural cannabislike compounds is called "anandamide," from the Sanskrit word "ananda," meaning bliss. In animal studies, Iversen says, anandamide "has essentially all of the pharmacological and behavioral actions of THC."

Researchers have shown that anandamide, like THC, seems to prevent the release of certain anxiety-producing chemicals in the brain. In general, Dr. Mackie says, the body's cannabislike compounds—or "cannabinoids"—"seem to have a function of keeping brain activity under control when there are a lot of neurons firing." Cannabinoids inhibit the chemical signals between nerve cells, slowing or suppressing certain kinds of transmission.

Other research is looking at ways to subvert this effect. For example, recent studies indicate that blocking the cannabinoid receptors in humans can cause the anti-munchies—curbing people's appetites and helping them lose weight (a finding that, of course, has the big drug companies salivating). Dr. Mackie says these test subjects show "decreased intake of sugary, fattening foods."

The study perhaps points toward at least one ultimate purpose for the cannabinoid system: to gear us up for pleasurable sensations. As Mackie suggests: "Maybe they serve a role in general hedonic-type responses."

In other words, forget what Momma says; your endogenous cannabinoids want to party.